It is well established that neutralizing antibodies (nAbs) against the HIV-1 envelope protein (Env) can be protective, as was demonstrated by passive immunization studies in non-human primates [1-3]. Therefore, the isolation of broadly nAbs (bnAbs) that can neutralize diversified HIV-1 strains is being pursued as a major path to the rational design of an effective HIV-1 vaccine [4].
Large numbers of potent new bnAbs have been recently isolated from multiple donors [5-11], mainly due to new technologies for isolating human monoclonal antibodies (mAbs) and the employment of a high-throughput neutralization screen system [5, 12-15]. Four types of new potent HIV-1 bnAbs have been identified. 1) The newly isolated ‘VRC01-like’ bnAbs [7, 8, 10] can block Env binding to primary receptor CD4 and they are superior to the previous CD4 binding site (CD4bs) nAb b12 [16]. 2) The newly isolated PGT series bnAbs [9] are glycan dependent and much more potent and broadly active than the old glycan-dependent nAb 2G12 [17], which can block Env binding to co-receptor CCR5. 3) The so-called ‘PG9-like’ bnAbs bind conserved conformational epitopes on the Env trimer of HIV-1 involving the V1/V2 and V3 regions and glycan, including PG9, PG16 [5] and CH01˜04 [11]. They are superior in breadth compared to previously identified strain-specific potent nAbs that recognize quaternary neutralizing epitopes (QNE) of HIV-1 Env [18, 19]. 4) The new isolated bnAb 10E8 targets the membrane proximal external region (MPER) of gp41 and is much more potent and broadly active than the old MPER nAbs 2F5 and 4E10 (J. Huang et al., Nature (2012) 491: 406-412).
These new bnAbs collectively neutralize the majority of the highly diversified HIV-1 strains [9]. However, these bnAbs also demonstrate some unusual features that may be major roadblocks for HIV-1 vaccine development. These highly mutated bnAbs were isolated from rare (<3%) “elite neutralizers” that were selected from more than a thousand HIV-1-infected persons [5, 11, 15]. Compared with the degree of somatic mutation in other Ab responses [13, 20], a common feature of these HIV-1 bnAbs is their apparent unusually high levels of mutation, especially in the heavy chain V (VH) genes [5-11]. This high level of mutation raises a high bar for a vaccine to generate this type of Ab response, which may be a major hurdle for HIV-1 vaccine development. In addition, some of these bnAbs showed auto/poly-reactivity [7, 8, 10], which is detrimental for B cell response. Currently, no HIV-1 vaccine candidates can elicit bnAb responses [4].
Thus, there continues to be a great need for HIV-1 vaccine candidates that can elicit bnAb responses, as well as potent HIV-1 bnAbs with improved characteristics.